{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T02:02:08Z","timestamp":1768528928001,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,31]]},"group-title":"Bioinformatics","reference-count":72,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"NIH Director's Transformative Research Award","award":["3R01AI169543"],"award-info":[{"award-number":["3R01AI169543"]}]},{"name":"Funda\u00e7\u00e3o de Amparo a\u2019 Pesquisa do Estado de S\u00e3o Paulo","award":["2020\/07158-2"],"award-info":[{"award-number":["2020\/07158-2"]}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"crossref","award":["305393\/2020-0"],"award-info":[{"award-number":["305393\/2020-0"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Scalable identification of antigen-specific antibodies from whole immune repertoire V(D)J sequences is a central challenge in biomedical engineering. We show that protein language models (PLMs) fine-tuned on antibody heavy-chain sequences can directly predict antigen specificity from unselected immune repertoires. We assessed our model, Antigen Specificity Predictor (ASPred), against SARS-CoV-2, influenza, and HIV-AIDS antigens, observing comparable predictive performance. In the whole immune repertoire V(D)J sequences of mice immunized with the SARS-CoV-2 spike protein\u2019s receptor-binding domain (RBD), ASPred identified antibody sequences specific to RBD. Several candidate sequences were validated, including one as a heavy chain-only nanobody with 20.7 nM dissociation constant. Molecular dynamics simulations supported the predicted interactions at coarse-grained and atomic levels. Benchmarking against Barcode-Enabled Antigen Mapping (BEAM) of B cell receptor sequence data had highly significant overlaps with ASPred predictions, suggesting scalability. The predicted SARS-CoV-2 binders differed substantially from training sequences, demonstrating generalization beyond sequence memorization. Together, we establish that heavy chain antibody sequences encode sufficient information for PLMs to infer specificity, offering a scalable framework for antibody discovery with broad applications.<\/jats:p>","DOI":"10.1101\/2025.10.30.685465","type":"posted-content","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T22:25:11Z","timestamp":1761949511000},"source":"Crossref","is-referenced-by-count":0,"title":["Fine-tuned protein language model identifies antigen-specific B cell receptors from immune repertoires"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9638-5222","authenticated-orcid":false,"given":"Karen","family":"Paco","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana Paco","family":"Mendivil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zihao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanaz","family":"Zebardast","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Davila","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan M.","family":"Mooney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peace","family":"Olatoyinbo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tristan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Bassi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faisal Bin","family":"Ashraf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel Condori","family":"Roman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan R.","family":"Felix","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rashid M.","family":"Alam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan A.","family":"Lay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3545-7583","authenticated-orcid":false,"given":"Malkiat S.","family":"Johal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4862-9292","authenticated-orcid":false,"given":"Karine G.","family":"Le Roch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilya","family":"Tolstorukov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeniffer B.","family":"Hernandez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando L. 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